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Streptomyces Coelicolor A3(2) Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Pleiotropic morphological and antibiotic deficiencies result from mutations in a gene encoding a tRNA-like product in Streptomyces coelicolor A3(2) Elizabeth J. Lawlor, Howard A. Baylis, and Keith F. Chater Agricultural and Food Research Council Institute of Plant Science Research, John Innes Institute, Norwich, NR4 7UH, UK In Streptomyces coelicolor, bldA mutants are defective in antibiotic production and the development of aerial hyphae and spores. Subcloning analysis showed that sequences spanning an NcoI site in cloned bldA ÷ DNA were needed to allow complementation of a bldA mutant. Nucleotide sequencing revealed a tRNA-like sequence 9 bp downstream from the NcoI site. Five independent bldA mutations all fell in a 16-bp region in the tRNA-like sequence, one of them changing the putative anticodon. In RNA dot-blot analysis, hybridization was detected with a probe specific for the tRNA-like transcript but not with a probe for "anti-tRNA-like" transcripts. The transcripts detected were all in the sah-soluble RNA fraction and accumulated relatively late in growth. It is postulated that bldA specifies a tRNA that would recognize the codon UUA (for leucine). This codon is very rare in Streptomyces genes [which generally contain >70 mole% (G + C)], suggesting a possible role for bldA in translational control of development. [Key Words: Differentiation; translational regulation; secondary metabolism; sporulation] Received September 3, 1987; revised version accepted September 17, 1987. The genus Streptomyces comprises Gram-positive soil was recently cloned on a Streptomyces temperate phage bacteria that grow as a branching vegetative mycelium, vector as a 5.6-kb PstI fragment (Piret and Chater 1985). on which aerial, sporogenous hyphae develop, presump- Here, we present the nucleotide sequence of a part of tively in response to nutritional limitation. Numerous this fragment containing the bldA gene. The location of antibiotics, including many that are valuable to man, are five bldA mutations in this sequence, coupled with produced by this group of bacteria, often at a time coin- analysis of bldA RNA, leads us to suggest that bldA ciding with the formation of aerial hyphae. specifies a tRNA for the rare leucine codon UUA and In different Streptomyces species, studies of morpho- that use of this codon may allow translational control of logical mutants have variously implicated arginine me- development. tabolism (Meade 1985), guanosine nucleotides (Ochi 1986), and extracellular diffusible factors (Khokhlov Results and discussion 1986) in both sporulation and antibiotic production (re- bldA mutations lie in a potential tRNA gene viewed by Chater 1984). In the genetically well-charac- terized S. coelicolor, bldA mutants are one of several Subcloning analysis showed that a BglII-PstI fragment classes of mutants defective in different stages of devel- of approximately 870 bp (fragment A, Fig. 1), derived opment while being apparently unimpaired in vegetative from the 5.6-kb PstI fragment originally cloned by Piret growth (Merrick 1976). On minimal agar medium con- and Chater (1985), gave bldA complementation results taining glucose or cellobiose as a carbon source, bldA identical to those obtained with the larger fragment mutant colonies produce no recognizable aerial hyphae (J.M. Piret and E.J. Lawlor, unpubl.). Following the ob- or spores; instead, the surface hyphae undergo frequent servation that cloning the 5.6-kb PstI fragment at high septation and fragmentation, which may be an aberrant copy number did not disrupt differentiation (J.M. Piret, form of the sporulation process (Chater and Merrick pets. comm.), further subcloning and complementation 1979). In addition, production of four quite different an- tests were carried out using a multicopy plasmid vector. tibiotics (two of them pigmented) made by the wild-type The results suggested that sequences spanning an NcoI strain is abolished. On other carbon sources, such as site (Fig. 1) were required for bldA expression because mannitol or maltose, aerial mycelium development and fragments B and C failed to complement a bldA muta- sporulation appear to occur normally, but antibiotic pro- tion (bldA62). Occasional wild-type recombinant colo- duction is not restored (Merrick 1976). The bldA gene nies were obtained with fragment C, indicating that the GENES & DEVELOPMENT1:1305-1310 © 1987 by Cold Spring Harbor Laboratory ISSN 0890-9369/87 $1.00 1305 Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Lawlor et al. PstI /~jcE Pstl 5.6kb I "V ORF tRNAI I I I I I i I I I B~E I Nrol PstI Fragment A I" " I 8?Obp "- tRNA ORF (complements bldA ) B~'E F-rogment B l- 4 %Obp ORF (foiled fo complemenf bldA62} Bgfll Fragment C {failed to comptemenf b~A62, but generoted Bid*recurbr~nts) | 330bp tRNA NcoI :ace Fragment O (used in ,ronscription onotysis) ~, ---------~"----'--'V | 160 bp tRNA .., ss probe I .. ss probe2 Figure 1. Fragments used for the localization, sequencing, and transcription analysis of bldA. Colonies obtained by transformation of S. coelicolor J395 and S. coelicolor J668 with a plasmid carrying fragment A all showed the Bld + phenotype; those obtained with plasmids carrying either fragment B or C generally retained the bldA mutant phenotype. Fragment D, inserted in M13mpl9, was used to generate two radioactively labeled single-stranded probes (ss probes 1 and 2; see Materials and methods) for transcription analysis (Fig. 4). bldA62 mutation lay to the right of the NcoI site. Frag- quence. Each mutation was in the potential tRNA gene ments B and C also failed to complement a second bldA (Fig. 3). mutation (bldA39); no wild-type recombinant colonies were seen among the few transformants obtained with The bldA gene specifies a small RNA that accumulates this particularly poorly transformable strain. late in growth The nucleotide sequence of fragment A was deter- mined (Fig. 2). Using the computer program "Frame" Although the double-stranded sequence potentially en- (Bibb et al. 1984), only one (truncated)potential open coding a tRNA was indeed bldA (or a part of it), it re- reading frame (ORF)was identified, beginning at a GTG mained possible that bldA was transcribed from right to triplet 69 bp from the left-hand end of fragment A, and left through this sequence. Using primed synthesis on reading leftward through the BglII site. The finding that single-stranded templates containing each orientation of bldA62 lay to the right of the NcoI site (see above) made the 160-base fragment D (Fig. 1), probe 1, specific for a it unlikely that this ORF was bldA. However, further tRNA-like transcript, and probe 2, specific for an anti- computer analysis of the nucleotide sequence using the tRNA-like transcript, were obtained. In Southern blot program of Staden (1980)revealed a potential tRNA gene analysis of total S. coelicolor DNA, using probe 1, only reading rightward from a position 9 bp to the right of the fragments of the sizes predicted from the restriction map NcoI site (Fig. 3). If this tRNA were the bldA gene of the bldA region were detected (results not shown). product, cleavage at the NcoI site would prevent com- The probes were therefore specific for bldA transcripts plementation of bldA mutants, because it would pre- and were used to analyze RNA that had been isolated at sumably separate the tRNA gene (and any genes down- different growth stages from a bldA + strain and frac- stream of it) from its promoter and from any transcribed tionated by precipitation in 3 M sodium acetate (in leader sequences that might be important for correct which RNA larger than about 6S is preferentially precip- processing of the transcript to give a mature tRNA. This, itated). Hybridization was detected only with probe 1 combined with the apparent absence of other potential and only with the soluble (sRNA)fraction that contains genes from the sequenced DNA, suggested that the po- smaller RNA species such as 5S RNA and tRNA (Fig. 4). tential tRNA gene was indeed bldA. It was strongest in RNA isolated from 36-hr cultures The nucleotide sequences of DNA fragments carrying (just before aerial hyphae appeared). Thus, only the po- five independent bldA mutations [including four pre- tential tRNA gene (and not its complementary strand) is viously shown to be alleles (Piret and Chater 1985)] were detectably transcribed, and its product accumulates as a determined. The 870-bp fragment A (Fig. 1)from each small RNA at a time compatible with its role in differ- mutant differed by only 1 bp from the wild-type se- entiation and antibiotic production. 1306 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Putative tRNA needed for development i ~;< GA T C T'T G GA_a_AG C T C CGTGGCGCGCGCGGC CACGAGGGTGGAC CGGTCGGCGATGGGTG ~ ~ AGAACCTTTCGAGGCACCGCGCGCGCCGGmC-CTCCCAC CTGGCCAGCCGCTACC~AC I 60 CGGTGGTCACGGG.a.AGGGCGICTCCTGTCGGTACGGCGTGTGCGGTCGGCACGGTGCGTGC [QCCACC%GTCqCCCTTCCCGCGAGGACAGCCATGCCGCACACGCCAGCCGTGCCACGCACG ",'20 GG~GGCAuGGTG~GTG,~. GGGCACGGTGCGTGCTGGGCACGGTGCGTGCGGTCGGCACGG CCACCGTGCCACACACGACCCGTGCCACGCACGACCCGTGCCACGCACGCCAGCCGTGCC 180 ~GCG~GCTCGGGGACGTTGTC:~.TCGmCCCGGTCGf~CGGCGCCCTGTAGTCAGCCGC ~ ACGCACGAGCCCCTGC.<ACAGTTAGCAGGGCCAGCTTGCCGC'GGACATCAGTCGGCGAC 240 ] bTCCGGTTCAGGG~GGCGAC'TTCGGTCGGACGGGCCGGGCCGGTGTCATACCTGCnGa<~ L~%GGCCAAGTCCCCCCGCTG-a-AGCCAOCCTGCCCGGCCCGG-CACAGTATGGACGCCTAC
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